CN101896464B - Sinomenine derivatives and processes for their synthesis - Google Patents

Sinomenine derivatives and processes for their synthesis Download PDF

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CN101896464B
CN101896464B CN200880120817.5A CN200880120817A CN101896464B CN 101896464 B CN101896464 B CN 101896464B CN 200880120817 A CN200880120817 A CN 200880120817A CN 101896464 B CN101896464 B CN 101896464B
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hydrogen
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halogen
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CN101896464A (en
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彼得·X·王
江涛
加里·L·坎特雷尔
戴维·W·伯布里克
博比·N·特拉维克
廖速波
约翰·布兰特
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Thought hundred Gex Co., Ltd.
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    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07—ORGANIC CHEMISTRY
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    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone

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Abstract

The invention generally provides processes and intermediate compounds useful for the production of sinomenine derivatives. In particular, the process may encompass synthetic routes for the production of (+)-sinomenine derivatives and their intermediates.

Description

Sinomenine derivate and their synthetic method
the cross reference of related application
The application requires the right of priority of the provisional application sequence number 61/014,099 of submitting on December 17th, 2007, and it is hereby incorporated by with its entirety.
Technical field
The present invention relates generally to for the preparation of the method for Sinomenine derivate and midbody compound.
Background technology
The alkaloid of having reported tuduranine-separate from the root of Stem of Orientoine (Sinomenium acutum), has anti-inflammatory, eases pain, reduces blood pressure and antiarrhythmic activity.The molecule of this separation and Stem of Orientoine plant are all used for the treatment of rheumatoid arthritis at Chinese Clinical.Although tuduranine rheumatoid arthritis symptom, it has some undesirable side effects.Therefore, the compound may with the structure relevant to tuduranine clinically will be more effective, has detrimental action still less simultaneously.
Summary of the invention
One aspect of the present invention comprises the compound of formula I:
Wherein:
R 1be selected from the alkyl of alkyl and replacement;
R 2and R 3independently selected from hydrogen, halogen, OH, NH 2, CN, the alkyl of alkyl and replacement;
R 4be selected from hydrogen, halogen, NH 2, CN, alkyl, the alkyl of replacement and OR 4a;
R 4abe selected from hydrogen and form the key containing ether ring part;
R 5and R 6independently selected from hydrogen, OH, NH 2, SH, the alkyl of alkyl and replacement, wherein R 5and R 6can form together and be selected from following group :=O ,=NOH ,=S ,=CHR 5awith
-O(CH 2) 2O-；
R 5abe selected from the alkyl of hydrogen, halogen, alkyl and replacement;
R 7be selected from hydrogen and OR 7a;
R 7abe selected from the alkyl of alkyl and replacement;
R 8be selected from the alkyl of hydrogen, alkyl and replacement;
R 9and R 10independently selected from hydrogen, OH, NH 2, SH, the alkyl of alkyl and replacement, wherein R 9and R 10can form be together selected from=O and=group of S;
R 11and R 12independently selected from hydrogen, OH, halogen, the alkyl of alkyl and replacement;
Y is selected from alkyl, the alkyl of replacement, carbonyl and alkyl-carbonyl;
M is 0 to 8 integer; With
-----is singly-bound or two key.
The present invention comprises that preparation comprises the method for the compound of formula 3 on the other hand.The method comprises according to following reaction scheme the compound that comprises formula 2 contacted with the compound of chloroformic acid 1-chloroethene ester with being selected from chloroformic acid vinyl acetate, then under the existence of protophobe or proton acceptor hydrolysis reaction mixture to form the compound that comprises formula 3:
Wherein
R 1, R 2, R 3and R 4independently selected from hydrogen, halogen, OH, NH 2, CN, the alkyl of alkyl and replacement;
R 5and R 6independently selected from hydrogen, OH, NH 2, SH, the alkyl of alkyl and replacement, wherein R 5and R 6can form together and be selected from following group :=O ,=NOH ,=S ,=CHR 5awith-O (CH 2) 2o-; With
R 5abe selected from the alkyl of hydrogen, halogen, alkyl and replacement; With
R 8and R 9independently selected from hydrogen, OH, NH 2, SH, the alkyl of alkyl and replacement, wherein R 8and R 9can form be together selected from following group :=O and=S.
The present invention provides preparation to comprise the method for the compound of formula 4 on the other hand.The method comprises and will have the compound of formula 3 and be selected from R according to following reaction scheme 7yX and R 7the compound of Y contacts to form the compound that comprises formula 4:
Wherein
R 1, R 2, R 3and R 4independently selected from hydrogen, halogen, OH, NH 2, CN, the alkyl of alkyl and replacement;
R 5and R 6independently selected from hydrogen, OH, NH 2, SH, the alkyl of alkyl and replacement, wherein R 5and R 6can form together and be selected from following group :=O ,=NOH ,=S ,=CHR 5awith-O (CH 2) 2o-; With
R 5abe selected from the alkyl of hydrogen, halogen, alkyl and replacement.
R 7be selected from the alkyl of alkyl and replacement;
R 8and R 9independently selected from hydrogen, OH, NH 2, SH, the alkyl of alkyl and replacement, wherein R 8and R 9can form be together selected from=O and=group of S;
X is halogen; With
Y is selected from alkyl, carbonyl and the alkyl-carbonyl of alkyl, replacement.
The present invention provides preparation to comprise the method for the compound of formula 5 on the other hand.The method comprises according to following reaction scheme the compound with formula 4a is contacted to form the compound that comprises formula 5 with X:
Wherein
R 1, R 2, R 3and R 4independently selected from hydrogen, halogen, OH, NH 2, CN, the alkyl of alkyl and replacement;
R 7be selected from the alkyl of alkyl and replacement;
R 8and R 9independently selected from hydrogen, OH, NH 2, SH, the alkyl of alkyl and replacement, wherein R 8and R 9can form be together selected from=O and=group of S;
X is halogen; With
Y is selected from alkyl, carbonyl and the alkyl-carbonyl of alkyl, replacement.
The present invention provides preparation to comprise the method for the compound of formula 6 on the other hand.The method comprises according to following reaction scheme the compound with formula 5a is contacted to form the compound that comprises formula 6 with proton acceptor:
Wherein
R 1, R 2and R 3independently selected from hydrogen, halogen, OH, NH 2, CN, the alkyl of alkyl and replacement;
R 4be selected from OH and NH 2;
R 7be selected from the alkyl of alkyl and replacement;
R 8and R 9independently selected from hydrogen, OH, NH 2, SH, the alkyl of alkyl and replacement, wherein R 8and R 9can form be together selected from=O and=group of S; With
X is halogen;
Y is selected from alkyl, the alkyl of replacement, carbonyl and alkyl-carbonyl; With
Z is selected from {-} O{-} and {-} NH{-}.
The present invention comprises that preparation comprises the method for the compound of formula 7 on the other hand.The method comprises according to following reaction scheme the compound with formula 6 is contacted to form the compound that comprises formula 7 with protophobe with scavenging agent:
Wherein
R 1, R 2and R 3independently selected from hydrogen, halogen, OH, NH 2, CN, the alkyl of alkyl and replacement;
R 7be selected from the alkyl of alkyl and replacement;
R 8and R 9independently selected from hydrogen, OH, NH 2, SH, the alkyl of alkyl and replacement, wherein R 8and R 9can form be together selected from=O and=group of S;
Y is selected from alkyl, the alkyl of replacement, carbonyl and alkyl-carbonyl; With
Z is selected from {-} O{-} and {-} NH{-}.
The present invention comprises the method for preparing compound 7 according to following reaction scheme on the other hand:
Wherein:
R 1be selected from the alkyl of alkyl and replacement;
R 2and R 3independently selected from hydrogen, halogen, OH, NH 2, CN, the alkyl of alkyl and replacement;
R 4and R 5independently selected from hydrogen, OH, NH 2, SH, the alkyl of alkyl and replacement, wherein R 4and R 5can form together and be selected from following group :=O ,=NOH ,=S ,=CHR 5awith-O (CH 2) 2o-;
R 5abe selected from the alkyl of hydrogen, halogen, alkyl and replacement;
R 6be selected from the alkyl of hydrogen, alkyl and replacement;
R 7and R 8independently selected from hydrogen, OH, NH 2, SH, the alkyl of alkyl and replacement, wherein R 7and R 8can form be together selected from=O and=group of S;
X is halogen;
Y is selected from alkyl, the alkyl of replacement, carbonyl and alkyl-carbonyl; With
Z is selected from {-} O{-} and {-} NH{-}.
Other side of the present invention and be described in following more detailed description.
Detailed Description Of The Invention
The invention provides method and the midbody compound of preparing Sinomenine derivate.The comparable tuduranine of these Sinomenine derivates is more special, more effectively and/or stronger.In addition, the comparable tuduranine of these Sinomenine derivates has side effect still less.
(I) Sinomenine derivate
The intermediate that Sinomenine derivate and can be used for is prepared Sinomenine derivate comprises formula I, (Ia), (Ib) and (Ic) substantially, as described below.
(a) there is the compound of formula I
In one embodiment of the invention, Sinomenine derivate comprises formula I:
Wherein:
R 1be selected from the alkyl of alkyl and replacement;
R 2and R 3independently selected from hydrogen, halogen, OH, NH 2, CN, the alkyl of alkyl and replacement;
R 4be selected from hydrogen, halogen, NH 2, CN, alkyl, the alkyl of replacement and OR 4a;
R 4abe selected from hydrogen and form the key containing ether ring part;
R 5and R 6independently selected from hydrogen, OH, NH 2, SH, the alkyl of alkyl and replacement, wherein R 5and R 6can form together and be selected from following group :=O ,=NOH ,=S ,=CHR 5awith-O (CH 2) 2o-;
R 5abe selected from the alkyl of hydrogen, halogen, alkyl and replacement;
R 7be selected from hydrogen and OR 7a;
R 7abe selected from the alkyl of alkyl and replacement;
R 8be selected from the alkyl of hydrogen, alkyl and replacement;
R 9and R 10independently selected from hydrogen, OH, NH 2, SH, the alkyl of alkyl and replacement, wherein R 9and R 10can form be together selected from=O and=group of S;
R 11and R 12independently selected from hydrogen, OH, halogen, the alkyl of alkyl and replacement;
Y is selected from alkyl, the alkyl of replacement, carbonyl and alkyl-carbonyl;
M is 0 to 8 integer; With
-----is singly-bound or two key.
In another embodiment, this compound comprises formula (I), wherein:
R 1be selected from the alkyl with 1 to 8 carbon atom, vinyl, aryl, cyclopropyl, cyclobutyl, {-} CH (CF 3) 2, {-} CH (CH 3) CF 3, {-} CH=CF 2{-} CH 2cF 3;
R 2be selected from hydrogen and halogen;
R 3for hydrogen;
R 4for OR 4a;
R 4abe selected from hydrogen and form the key containing ether ring part;
R 5and R 6independently selected from hydrogen, OH and NH 2, wherein R 5and R 6can form together=O;
R 7as above definition;
R 8, R 9, R 10, R 11and R 12the hydrogen of respectively doing for oneself;
Y is selected from {-} CH 2{-} and {-} CO{-}; With
M is 0.
Of this embodiment preferred aspect, R 7for OR 7aand R 7abe selected from and there is 1 to 8 alkyl of carbon atom and the alkyl of replacement.At the illustrative aspects of this scheme, R 7afor methyl.
In another embodiment, this compound comprises formula (I), wherein:
R 1for cyclopropyl;
R 2for halogen;
R 3for hydrogen;
R 4for OR 4a; R 4abe selected from hydrogen and form the key containing ether ring part;
R 5and R 6independently selected from hydrogen, OH and NH 2, wherein R 5and R 6can form together=O;
R 7be selected from hydrogen and OR 7a;
R 7abe selected from and there is 1 to 8 alkyl of carbon atom and the alkyl of replacement;
R 8, R 9, R 10, R 11and R 12the hydrogen of respectively doing for oneself;
Y is selected from {-} CH 2{-} and {-} CO{-}; With
M is 0.
To this embodiment, preferably, R 2for bromine or chlorine.At the illustrative aspects of this embodiment, R 7for OR 7aand R 7afor methyl.
(b) there is the compound of formula (Ia)
In another embodiment of the present invention, this compound comprises formula (Ia):
Wherein:
R 2be selected from hydrogen, halogen, OH, NH 2, CN, the alkyl of alkyl and replacement;
R 5and R 6independently selected from hydrogen, OH, NH 2, SH, the alkyl of alkyl and replacement, wherein R 5and R 6can form together and be selected from following group :=O ,=NOH ,=S ,=CHR 5awith-O (CH 2) 2o-;
R 5abe selected from the alkyl of hydrogen, halogen, alkyl and replacement;
R 7be selected from hydrogen and OR 7a;
R 7abe selected from the alkyl of alkyl and replacement;
R 8be selected from the alkyl of hydrogen, alkyl and replacement;
R 9and R 10independently selected from hydrogen, OH, NH 2, SH, the alkyl of alkyl and replacement, wherein R 9and R 10can form be together selected from=O and=group of S;
Z is selected from {-} O{-}, {-} S{-} and {-} NH{-}; With
-----is singly-bound or two key.
In another embodiment, this compound comprises formula (Ia), wherein:
R 2be selected from halogen and hydrogen;
R 5and R 6independently selected from hydrogen, OH and NH 2wherein R 5and R 6can form together=O;
R 7for OR 7aand R 7abe selected from and there is 1 to 8 alkyl of carbon atom and the alkyl of replacement;
R 8, R 9and R 10the hydrogen of respectively doing for oneself; With
Z is oxygen.
Of this embodiment preferred aspect, R 2for halogen and R 7afor methyl.Preferably, this halogen is bromine or chlorine.
(c) there is the compound of formula (Ib)
In another embodiment, this compound comprises formula (Ib):
Wherein:
R 2be selected from hydrogen, halogen, OH, NH 2, CN, the alkyl of alkyl and replacement;
R 4be selected from hydrogen, halogen, NH 2, CN, alkyl, the alkyl of replacement and OR 4a.
R 4abe selected from hydrogen and form the key containing ether ring part;
R 5and R 6independently selected from hydrogen, OH, NH 2, SH, the alkyl of alkyl and replacement, wherein R 5and R 6can form together and be selected from following group :=O ,=NOH ,=S ,=CHR 5awith-O (CH 2) 2o-;
R 5abe selected from the alkyl of hydrogen, halogen, alkyl and replacement;
R 7be selected from hydrogen and OR 7a;
R 7abe selected from the alkyl of alkyl and replacement; With
-----is singly-bound or two key.
In another embodiment, this compound comprises formula (Ib), wherein:
R 2be selected from hydrogen and halogen;
R 4for OR 4a;
R 4abe selected from hydrogen and form the key containing ether ring part;
R 5and R 6independently selected from hydrogen, OH and NH 2, wherein R 5and R 6can form together=O; With
R 7for OR 7aand R 7abe selected from and there is 1 to 8 alkyl of carbon atom and the alkyl of replacement.
At the illustrative aspects of this embodiment, R 2for halogen and R 7afor methyl.Preferably, this halogen is bromine or chlorine.
(d) there is the compound of formula (Ic)
In another embodiment, this compound comprises formula (Ic):
Wherein:
R 2be selected from hydrogen, halogen, OH, NH 2, CN, the alkyl of alkyl and replacement;
R 4be selected from hydrogen, halogen, NH 2, CN, alkyl, the alkyl of replacement and OR 4a;
R 4abe selected from hydrogen and form the key containing ether ring part;
R 5and R 6independently selected from hydrogen, OH, NH 2, SH, the alkyl of alkyl and replacement, wherein R 5and R 6can form together and be selected from following group :=O ,=NOH ,=S ,=CHR 5awith-O (CH 2) 2o-; With
R 5abe selected from the alkyl of hydrogen, halogen, alkyl and replacement.
In another embodiment, this compound comprises formula (Ic), wherein:
R 2be selected from hydrogen and halogen;
R 4for OR 4a;
R 4abe selected from hydrogen and form the key containing ether ring part; With
R 5and R 6independently selected from hydrogen, OH and NH 2, wherein R 5and R 6can form together=O.
At the illustrative aspects of this embodiment, R 2for halogen.Preferably, this halogen is bromine or chlorine.
(e) exemplary compounds
The limiting examples with formula I, (Ia), (Ib) or exemplary compounds (Ic) is listed in Table A.
Table A
Table A
Table A
Above-claimed cpd can have (-) or (+) three-dimensional chemical configuration about the rotation of polarized light.More specifically, each chiral centre can have R or S configuration.
For being easy to discuss, the annular atoms of the parent nucleus morphinan structure of mentioning is herein by following numbering:
Carbon 13,14 and 9 is chiral centre.Therefore, the configuration with structure (I), (Ib) or compound of the present invention (Ic) can be RRS for C13, C14 and C9, RSS, SRR, or SSR.Equally, the configuration of compound 8-1 and 9-1 can be RRS for C13, C14 and C9, RSS, SRR or SSR.In exemplary, the configuration of compound 8-1 and 9-1 can be (-) RSS.
Connect in the Sinomenine derivate of carbon 4 and 5 containing ether ring therein, have four chiral carbon, that is, and carbon 5,13,14 and 9.Therefore, the configuration with the compound of the present invention of formula (Ia) can be RRRS for C5, C13, C 14 and C9, RRSS, SRRS, SRSS, RSRR, RSSR, SSRR, or SSSR.Equally, compound 10-1,11-1, the configuration of 12-1 and 13-1 can be RRRS about C5, C13, C14 and C9, RRSS, SRRS, SRSS, RSRR, RSSR, SSRR, or SSSR.In exemplary, compound 10-1,11-1, the configuration of 12-1 and 13-1 can be (+) SRSS.
The present invention also comprises above-mentioned any salt with formula (I), (Ia), (Ib) and compound (Ic).Exemplary salt includes but not limited to hydrochloride, hydrobromate, phosphoric acid salt, vitriol, mesylate, acetate, formate, tartrate, maleate, malate, Citrate trianion, isocitrate, succinate, lactic acid salt, gluconate, glucuronate, pyruvate salt, oxalate, fumarate, propionic salt, aspartate, glutaminate, benzoate, methyl fluoride compound (methyl fluoride), Methochloride (methyl chloride), MB (methyl bromide), methyl-iodide compound (methyl iodide), Deng.
(II) prepares the method for Sinomenine derivate
The present invention provides on the other hand preparation to have formula (I), (Ia), (Ib) and Sinomenine derivate (Ic) or can be used for the method for the intermediate of preparing Sinomenine derivate.Think that route of synthesis as herein described can be used for preparation (+/-)-Sinomenine derivate, in illustrative aspects of the present invention, the method comprises preparation (+)-Sinomenine derivate.For explanatory object, reaction scheme 1 is described and is prepared according to an aspect of the present invention compound 7.
reaction scheme 1:
Wherein:
R 1be selected from the alkyl of alkyl and replacement;
R 2and R 3independently selected from hydrogen, halogen, OH, NH 2, CN, the alkyl of alkyl and replacement;
R 4and R 5independently selected from hydrogen, OH, NH 2, CN, the alkyl of alkyl and replacement; Wherein R 4and R 5can form together and be selected from following group :=O ,=NOH ,=S ,=CHR 5awith-O (CH 2) 2o-;
R 5abe selected from the alkyl of hydrogen, halogen, alkyl and replacement;
R 6be selected from the alkyl of hydrogen, alkyl and replacement;
R 7and R 8independently selected from hydrogen, OH, NH 2, SH, the alkyl of alkyl and replacement, wherein R 7and R 8can form be together selected from=O and=group of S;
X is halogen;
Y is selected from alkyl, the alkyl of replacement, carbonyl and alkyl-carbonyl; With
Z is selected from oxygen, nitrogen and sulphur.
Of this embodiment alternative aspect, the composition of this reaction comprises:
R 1be selected from the alkyl with 1 to 8 carbon atom, vinyl, aryl, cyclopropyl, cyclobutyl, {-} CH (CF 3) 2, {-} CH (CH 3) CF 3, {-} CH=CF 2{-} CH 2cF 3,
R 2and R 3independently selected from hydrogen, halogen, OH, NH 2, CN, acyl group, alkyl, thiazolinyl, aryl, alkoxyl group and alkylamino;
R 4and R 5independently selected from hydrogen, OH and alkoxyl group, wherein R 4and R 5can form together and be selected from following group :=O ,=NOH and-O (CH 2) 2o-;
R 6be selected from hydrogen and alkyl;
R 7and R 8independently selected from hydrogen, OH and NH 2, wherein R 7and R 8can form together=O;
X is selected from bromine and chlorine;
Y is selected from {-} CH 2{-} and {-} CO{-}; With
Z is oxygen.
In this scheme on the other hand, R 1for cyclopropyl; R 2for hydrogen; R 3for {-} O (CH 2) mcH 3; R 4and R 5formation=O together; R 6, R 7and R 8the hydrogen of respectively doing for oneself; And m is 0 to 8.In illustrative aspects, X is that bromine and m are 0.
(a) steps A: compound 2 is to the conversion of compound 3
In the method steps A, substrate compounds 2 contacts with chloroformic acid vinyl acetate or chloroformic acid 1-chloroethene ester, then under the existence of the dilute solution of protophobe or proton acceptor hydrolysis reaction mixture to form compound 3.
This reaction can be carried out under the existence of solvent.This solvent can be aprotic solvent.The limiting examples of aprotic solvent comprises ether solvents, acetone, acetonitrile, benzene, methylene diethyl ether, N, dinethylformamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), N, N-dimethyl propylene acid amides, 1, 3-dimethyl-3, 4, 5, 6-tetrahydrochysene-2 (1H)-pyrimidone (DMPU), 1, 3-dimethyl-2-imidazolidone (DMI), 1, 2-glycol dimethyl ether (DME), N,N-DIMETHYLACETAMIDE (DMAC), N-Methyl pyrrolidone (NMP), ethyl acetate, ethyl formate, ethyl methyl ketone, methane amide, isobutyl methyl ketone, hexamethylphosphoramide, methyl acetate, N-methylacetamide, N-METHYLFORMAMIDE, methylene dichloride, oil of mirbane, Nitromethane 99Min., propionitrile, tetramethylene sulfone, tetramethyl-urea, tetrahydrofuran (THF) (THF), toluene, trichloromethane.In one embodiment, aprotic solvent can be dimethyl formamide, dimethyl sulfoxide (DMSO) ， diox, methane amide, or N-methylacetamide.
The weight ratio of aprotic solvent and compound 2 can be approximately 1: 1 to approximately 20: 1.In one embodiment, the weight ratio of solvent and compound 2 can be approximately 1: 1 to approximately 3: 1.In another embodiment, the weight ratio of solvent and compound 2 can be approximately 6: 1 to approximately 12: 1.In another embodiment, the weight ratio of solvent and compound 2 can be approximately 12: 1 to approximately 20: 1.In one embodiment, the weight ratio of solvent and compound 2 can be approximately 3: 1 to approximately 6: 1.
Conventionally then reaction mixture is processed to form compound 3 by the dilute solution of protophobe or proton acceptor.Conventionally the pKa that, this protophobe has is less than approximately 6.Suitable protophobe includes, but not limited to HOAc, HCO 2h, H 2cO 3, MeSO 3h, poly H 3pO 4, H 3pO 4, H 2sO 4, HCl, HBr, HI, CF 3sO 3h and to methyl toluenesulphonic acids.The pKa that this proton acceptor has is conventionally approximately 7 to approximately 13.The suitable proton acceptor with this feature comprise borate (as, for example, NaBO 3), binary and ternary phosphates (as, for example, Na 2hPO 4and Na 3pO 4, etc.), supercarbonate (as, for example, NaHCO 3, KHCO 3, LiCO 3, etc.), carbonate (as, for example, Na 2cO 3, K 2cO 3, Li 2cO 3, etc.), organic bases (as, for example, pyridine, triethylamine, diisopropyl ethyl amine, N-methylmorpholine, N, N-dimethyl aminopyridine), and above-mentioned any mixture.In preferred embodiments, this proton acceptor can be NaHCO 3, KHCO 3, LiCO 3, Na 2cO 3, K 2cO 3, Li 2cO 3, or its mixture.In an exemplary, this proton acceptor can be NaHCO 3.
The amount of the reactant contacting with compound 2 can change and will change.Conventionally, compound 2 can be approximately 1: 2: 1 to approximately 1: 20: 20 with the weight ratio of chloroformic acid vinyl acetate or chloroformic acid 1-chloroethene ester and protophobe or proton acceptor.In one embodiment, compound 2 can be approximately 1: 2: 1 to approximately 1: 4: 4 with the weight ratio of chloroformic acid vinyl acetate or chloroformic acid 1-chloroethene ester and protophobe or proton acceptor.In another embodiment, compound 2 can be approximately 1: 4: 4 to approximately 1: 10: 10 with the weight ratio of chloroformic acid vinyl acetate or chloroformic acid 1-chloroethene ester and protophobe or proton acceptor.In another embodiment, compound 2 can be approximately 1: 10: 10 to approximately 1: 20: 20 with the weight ratio of chloroformic acid vinyl acetate or chloroformic acid 1-chloroethene ester and protophobe or proton acceptor.In one embodiment, compound 2 can be approximately 1: 3: 3 to approximately 1: 12: 12 with the weight ratio of chloroformic acid vinyl acetate or chloroformic acid 1-chloroethene ester and protophobe or proton acceptor.
This reaction can be carried out the temperature range of approximately 50 DEG C to approximately 120 DEG C.In one embodiment, the temperature of this reaction can be approximately 100 DEG C to approximately 120 DEG C.In another embodiment, the temperature of this reaction can be approximately 80 DEG C to approximately 100 DEG C.In one embodiment, the temperature of this reaction can be approximately 50 DEG C to approximately 80 DEG C.This reaction is preferably carried out under environmental stress, and preferably for example, in inert atmosphere (, nitrogen or argon gas), carries out.
Conventionally, make this reaction carry out time enough until react completely, it for example, is determined by chromatography (, HPLC).In this article, " reaction completely " typically refers to each amount of substance while beginning than reaction, the compound 1 that reaction mixture comprises remarkable reduction, and the compound 2 of remarkable increasing amount.
The productive rate of compound 3 can change.Conventionally, the productive rate of compound 3 can be approximately 40% to approximately 70%.In one embodiment, the productive rate of compound 3 can be approximately 40% to approximately 50%.In another embodiment, the productive rate of compound 3 can be approximately 50% to approximately 60%.In another embodiment, the productive rate of compound 3 can be approximately 60% to approximately 70%.
(b) step B: compound 3 is to the conversion of compound 4
In the step B of the method, compound 3 use R 1yX alkylation or use R 1y carries out reduction amination to form compound 4.R 1, Y and X as above define.Preferably, Y is-CH 2-or-CHO.The method comprises compound 3 and R 7yX or R 7y contacts to form compound 4.
This reaction can be carried out under the existence of solvent.This solvent can be aprotic solvent.Suitable aprotic solvent is as described in the method steps A.Conventionally, the weight ratio of solvent and compound 3 can be approximately 1: 1 to approximately 20: 1.In one embodiment, the weight ratio of solvent and compound 3 can be approximately 1: 1 to approximately 4: 1.In another embodiment, the weight ratio of solvent and compound 3 can be approximately 4: 1 to approximately 20: 1.
The R contacting with compound 3 1yX or R 1the amount of Y can change.Conventionally compound 3 and R, 1yX or R 1the weight ratio of Y can be approximately 1: 1 to approximately 1: 3.In one embodiment, compound 3 and R 1yX or R 1the weight ratio of Y can be approximately 1: 1 to approximately 1: 2.In another embodiment, compound 3 and R 1yX or R 1the weight ratio of Y can be approximately 1: 2 to approximately 1: 3.In one embodiment, compound 3 and R 1yX or R 1the weight ratio of Y can be approximately 1: 1.1 to approximately 1: 1.5.
The temperature of this reaction can be approximately 20 DEG C to approximately 100 DEG C.In one embodiment, the temperature of this reaction can be approximately 20 DEG C to approximately 40 DEG C.In another embodiment, the temperature of this reaction can be approximately 40 DEG C to approximately 70 DEG C.In another embodiment, the temperature of this reaction can be approximately 70 DEG C to approximately 100 DEG C.This reaction is preferably carried out under environmental stress, and preferably for example, in inert atmosphere (, nitrogen or argon gas), carries out.
Conventionally, make this reaction carry out time enough until react completely, it is by technology known in the art, as chromatography is determined.Conventionally, the productive rate of compound 4 can be approximately 60% to approximately 80%.In one embodiment, the productive rate of compound 4 can be approximately 60% to approximately 70%.In another embodiment, the productive rate of compound 4 can be approximately 70% to approximately 80%.
(c) step C: compound 4 is to the conversion of compound 5
In the step C of the method, compound 4 and X 2contact is to form compound 5.X 2as above definition.
This reaction can be carried out under the existence of solvent.This solvent can be organic solvent.Suitable organic solvent includes, but not limited to the alkane solvent (comprising naphthenic hydrocarbon) of alkane and replacement, aromatic hydrocarbon, and ester, ether, ketone, its combination, etc.Spendable concrete organic solvent comprises, for example, and acetonitrile, benzene, butylacetate, t-butyl methyl ether, tertiary butyl methyl ketone, chlorobenzene, chloroform, methyl chloride, hexanaphthene, methylene dichloride, ethylene dichloride, ether, ethyl acetate, fluorobenzene, heptane, hexane, isobutyl methyl ketone, isopropyl acetate, methyl ethyl ketone, methyltetrahydrofuran, pentyl acetate, n-propyl acetate, tetrahydrofuran (THF), toluene, its combination, etc.In preferred embodiments, this organic solvent can be benzene, chloroform, ether, ethyl acetate, heptane, hexane, or toluene.
Conventionally, the weight ratio of organic solvent and compound 4 can be approximately 5: 1 to approximately 50: 1.In one embodiment, the weight ratio of organic solvent and compound 4 can be approximately 5: 1 to approximately 20: 1.In another embodiment, the weight ratio of organic solvent and compound 4 can be approximately 20: 1 to approximately 50: 1.
Generally speaking, the X of approximately 2 molar equivalents 2contact with compound 4.In one embodiment, compound 4 and X 2weight ratio can be approximately 1: 2 to approximately 1: 2.5.In one embodiment, compound 4 and X 2weight ratio can be approximately 1: 2.1.
Optionally, in one embodiment, alkali can be added into the reaction of step C.Conventionally at the temperature that, described alkali carries out in reaction, be liquid.For example, triethylamine is a kind of this suitable alkali.Do not combine with theory, it has been generally acknowledged that adding alkali to step C can neutralize the acid (for example, the hydrogen bromide in the time that X is bromine) of formation, to prevent that acid from reacting with reactant or product.In another optional embodiment, can add halogen scavenger.For example, in the time that halogen is bromine, can add bromine scavenging agent as 2,3-dimethyl-1,3-butadiene.
The temperature of this reaction can be approximately-30 DEG C to approximately 0 DEG C, and more preferably from about-20 DEG C to approximately-5 DEG C.In one embodiment, the temperature of this reaction can be approximately-20 DEG C to approximately-10 DEG C.In another embodiment, the temperature of this reaction can be approximately-10 DEG C to approximately-5 DEG C.This reaction is preferably carried out under environmental stress, and preferably for example, in inert atmosphere (, nitrogen or argon gas), carries out.
Conventionally, make this reaction carry out time enough until react completely, it uses standard technique to determine.The productive rate of compound 5 can change according to reaction conditions.Conventionally, the productive rate of compound 5 can be approximately 20% to approximately 70%.In one embodiment, the productive rate of compound 5 can be approximately 20% to approximately 40%.In another embodiment, the productive rate of compound 5 can be approximately 40% to approximately 60%.In another embodiment, the productive rate of compound 5 can be approximately 60% to approximately 70%.
(d) step D: compound 5 is to the conversion of compound 6
The method step D comprises ring-closure reaction.The method comprises and compound 5 is contacted to form compound 6 with proton acceptor.
This reaction can be carried out under the existence of solvent.This solvent can be aprotic solvent, protonic solvent, or its mixture.Suitable aprotic solvent is as described in the method steps A.The limiting examples of suitable protonic solvent comprises methyl alcohol, ethanol, Virahol, n-propyl alcohol, isopropylcarbinol, the trimethyl carbinol, propyl carbinol, formic acid, acetic acid and water.In one embodiment, this solvent can be aprotic solvent or its combination.In another embodiment, this solvent can be protonic solvent or its combination.In another embodiment, this solvent can be solvent system, wherein its combination that comprises aprotic solvent and protonic solvent.
Conventionally, the weight ratio of solvent or solvent system and compound 5 can be approximately 5: 1 to approximately 50: 1.In one embodiment, the weight ratio of solvent or solvent system and compound 5 can be approximately 5: 1 to approximately 20: 1.In another embodiment, the weight ratio of solvent or solvent system and compound 5 can be approximately 20: 1 to approximately 50: 1.
Conventionally the pKa, having for the proton acceptor of this step is greater than approximately 12.The limiting examples with the suitable proton acceptor of this feature comprise the oxyhydroxide of alkali and alkaline earth metal ions (as, for example, NaOH and Ca (OH) 2deng), and 1 family's salt of carbanion, acid amides and hydride (as, for example, butyllithium, sodium amide (NaNH 2), sodium hydride (NaH), etc.).In a preferred embodiment, this proton acceptor can be NaOH, KOH, LiOH, Ca (OH) 2or NaH.In an exemplary, this proton acceptor can be NaOH.
It is approximately 13 or higher that the amount that is added into the proton acceptor of this reaction is enough to keep the pH of reaction mixture conventionally.Conventionally, compound 5 can be approximately 1: 1.5 to approximately 1: 20 with the weight ratio of proton acceptor.In one embodiment, compound 5 can be approximately 1: 1.5 to approximately 1: 5 with the weight ratio of proton acceptor.In another embodiment, compound 5 can be approximately 1: 5 to approximately 1: 20 with the weight ratio of proton acceptor.
The temperature of this reaction can be approximately-30 DEG C to approximately 0 DEG C, and more preferably from about-20 DEG C to approximately-5 DEG C.In one embodiment, the temperature of this reaction can be approximately-20 DEG C to approximately-10 DEG C.In another embodiment, the temperature of this reaction can be approximately-10 DEG C to approximately-5 DEG C.This reaction is preferably carried out under environmental stress, and preferably for example, in inert atmosphere (, nitrogen or argon gas), carries out.
Conventionally, make this reaction carry out time enough until react completely, it uses technology well known by persons skilled in the art to determine.The productive rate of the compound 6 of preparing from compound 5 can change according to reaction conditions.Conventionally, the productive rate of compound 6 can be approximately 70% to approximately 95%.In one embodiment, the productive rate of compound 6 can be approximately 70% to approximately 80%.In another embodiment, the productive rate of compound 6 can be approximately 80% to approximately 90%.In another embodiment, the productive rate of compound 6 can be approximately 90% to approximately 95%.
(e) step e: compound 6 is to the conversion of compound 7
In the method step e, compound 6 contacts to form compound 7 with protophobe with scavenging agent.
This reaction can be carried out under the existence of solvent.This solvent can be aprotic solvent, as described in detail in above the method steps A.Conventionally, the weight ratio of solvent or solvent system and compound 6 can be approximately 5: 1 to approximately 50: 1.In one embodiment, the weight ratio of solvent or solvent system and compound 6 can be approximately 5: 1 to approximately 20: 1.In another embodiment, the weight ratio of solvent or solvent system and compound 6 can be approximately 20: 1 to approximately 50: 1.
Conventionally, this scavenging agent is alcohol scavenging agent.This alcohol can have approximately 1 to approximately 8 carbon atom.In an exemplary, alcohol scavenging agent is methyl alcohol scavenging agent.The limiting examples of suitable alcohol scavenging agent comprises P 2o 5, POCl 3, POBr 3, PCl 3, SOCl 2, SOBr 2, MeSO 2cl, (MeSO 2) 2o, SO 3, (CF 3sO 2) 2o and (CF 3cO) 2o.In a preferred embodiment, this alcohol scavenging agent can be POCl 3.
The PKa that this protophobe has is conventionally less than approximately 0.The suitable protophobe with this feature includes, but not limited to MeSO 3h, poly H 3pO 4, H 3pO 4, H 2sO 4, HCl, HBr, HClO 4, HI, HNO 3, CF 3sO 3h, to methyl toluenesulphonic acids, HClO 3, HBrO 4, HIO 3and HIO 4.In one embodiment, this protophobe can be MeSO 3h, poly H 3pO 4, H 3pO 4, H 2sO 4, HCl, HBr, CF 3sO 3h and to methyl toluenesulphonic acids.In a preferred embodiment, this protophobe can be MeSO 3h.
Conventionally, compound 6 is approximately 1: 0.5: 2 to approximately 1: 2: 20 with the weight ratio of scavenging agent and protophobe.In one embodiment, compound 6 is approximately 1: 0.5: 2 to approximately 1: 1: 5 with the weight ratio of scavenging agent and protophobe.In an alternative embodiment, compound 6 is approximately 1: 1: 5 to approximately 1: 2: 20 with the weight ratio of scavenging agent and protophobe.
The temperature of this reaction can be approximately 0 DEG C to approximately 100 DEG C, and more preferably from about 20 DEG C to approximately 45 DEG C.In one embodiment, the temperature of this reaction can be approximately 20 DEG C to approximately 35 DEG C.In another embodiment, the temperature of this reaction can be approximately 35 DEG C to approximately 45 DEG C.This reaction is preferably carried out under environmental stress, and preferably for example, in inert atmosphere (, nitrogen or argon gas), carries out.
Conventionally, make this reaction carry out time enough until react completely, it uses standard technique to determine.The productive rate of compound 7 is generally approximately 20% to approximately 60%.In one embodiment, the productive rate of compound 7 can be approximately 20% to approximately 40%.In another embodiment, the productive rate of compound 7 can be approximately 40% to approximately 50%.In another embodiment, the productive rate of compound 7 can be approximately 50% to approximately 60%.
(f) prepare exemplary compounds
Compound 7 and some midbody compound described in reaction scheme 1, as compound 4 and 6, can be used for preparing one or more and have formula (I), (Ia), (Ib) or Sinomenine derivate compound (Ic).As limiting examples, reducible compound 4,6 and 7 is to form respectively compound 8-1,10-1 and 13-1.Can use multiple method of reducing, comprise, for example, chemical reduction, catalytic reduction, etc.Representative reductive agent for chemical reduction comprises hydride (for example, hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, etc.), or metal is (for example, tin, zinc, or iron) or metallic compound (for example, chromium chloride, chromium acetate, etc.) and organic or inorganic acid (for example, formic acid, acetic acid, propionic acid, trifluoroacetic acid, tosic acid, hydrochloric acid, Deng) combination, means of samarium iodide, and other.In an exemplary, this reductive agent can be sodium borohydride (NaBH 4).The representative reductive agent using together with hydrogen for catalytic reduction method comprises conventional catalyzer, for example, platinum catalyst (for example, platinum black, colloidal platinum, platinum oxide, platinum plate, platinum silk floss (platinum sponge), platinum filament, Deng), palladium catalyst (for example, palladium black, palladium/barium carbonate, palladium/barium sulfate, colloidal palladium, palladium/carbon, palladium hydroxide/carbon, palladous oxide, palladium silk floss (palladium sponge), Deng), nickel catalyzator (for example, nickel oxide, Raney nickel, reduced nickel, Deng), cobalt catalyst (for example, Raney cobalt, reduction cobalt, Deng), iron catalyst (for example, iron in Ruan, reduced iron, Ullmann iron, Deng), and other.For preparing compound 8-1 and 10-1, may need the combination of chemical reduction and catalytic reduction.
And compound 4-1 and 6-1 (referring to the reaction scheme 2 in embodiment) can experience reduction amination to form respectively compound 9-1 and 11-1.Suitable reactant and condition are normally known in the art.As an example, reduction amination can be under the existence of hydrogen carries out with together with palladium, platinum or nickel catalyzator as defined above.Or this reduction amination can comprise hydrogen and Noyori catalyzer, formic acid and tertiary amine.
In addition, compound 7-1 (referring to the reaction scheme 2 in embodiment) can experience hydrogenation to form compound 12-1.This hydrogenation can be catalysis, under the existence of hydrogen and metal catalyst as detailed above.Suitable metal catalyst comprises platinum, palladium, rhodium, ruthenium, etc.Those skilled in the art will be familiar with reaction conditions and other variable.
Definition
Term " acyl group " is as used separately at this or as the part of other group, representing to remove from the COOH base of organic carboxyl acid the part that hydroxyl forms, for example, RC (O)-, wherein R is R 1, R 1o-, R 1r 2n-or R 1s-, R 1for alkyl, assorted alkyl or the heterocyclic radical replacing, and R 2for the alkyl of hydrogen, alkyl or replacement.
Term " acyloxy ", as used separately at this or as the part of other group, representing the acyl group that connects (O) bonding by oxygen as above, for example, RC (O) O-, wherein R and the same definition in term " acyl group ".
Term used herein " alcohol scavenging agent " is for can react and discharge sour reagent simultaneously with alcohol.
Following group described in term as herein described " alkyl ", and it is preferably the low alkyl group that comprises 1 to 8 carbon atom at main chain, and be up to 20 carbon atoms.That they can be straight or branched or ring-type, and comprise methyl, ethyl, propyl group, sec.-propyl, butyl, hexyl etc.
Term as herein described " alkaryl " or " alkylaryl " have been described following group, and it is preferably the aryl with low-grade alkyl substituent, as tolyl, ethylphenyl or methyl naphthyl.
Following group described in term as herein described " thiazolinyl ", and it is preferably the low-grade alkenyl that comprises 2 to 8 carbon atoms at main chain, and be up to 20 carbon atoms.That they can be straight or branched or ring-type, and comprise vinyl, propenyl, pseudoallyl, butenyl, isobutenyl, hexenyl, etc.
Following group described in term as herein described " alkynyl ", and it is preferably the low-grade alkynyl that comprises 2 to 8 carbon atoms at main chain, and be up to 20 carbon atoms.They can be straight or branched, and comprise ethynyl, proyl, butynyl, isobutyl alkynyl, hexin base, etc.
Following group described in term as herein described " aralkyl ", and it is preferably the low alkyl group that comprises 1 to 8 carbon atom with aryl substituent, as benzyl, phenylethyl or 2-naphthyl methyl.
Term " aromatics ", as used separately at this or as the part of other group, representing optional homocyclic ring or the heterocyclic aromatic group replacing.These aromatic groups are preferably the monocycle, dicyclo or three cyclic groups that comprise 6 to 14 atoms at loop section.Term " aromatics " comprises with undefined " aryl " and " heteroaryl ".
Term " aryl ", as used separately at this or as the part of other group, representing the optional homocyclic ring aromatic group replacing, the monocycle or the bicyclic radicals that preferably comprise 6 to 12 carbon at loop section, as the phenyl of phenyl, xenyl, naphthyl, replacement, the xenyl of replacement or the naphthyl of replacement.The phenyl of phenyl and replacement is preferred aryl.
Term " halogen " or " halogen ", as used separately at this or as the part of other group, referring to chlorine, bromine, fluorine and iodine.
Term " heteroatoms " refers to the atom except carbon and hydrogen.
Term " heterocyclic radical " or " heterocycle ", as used separately at this or as the part of other group, represent optional replacement, complete saturated or undersaturated, monocycle or dicyclo, aromatics or non-aromatic group, it has at least one heteroatoms at least one ring, and preferably has 5 or 6 atoms at each ring.This heterocyclic radical preferably has 1 or 2 Sauerstoffatom and/or 1 to 4 nitrogen-atoms in ring, and is connected to the remainder of molecule by carbon or heteroatoms.Exemplary heterocyclic radical comprises the heteroaromatic of the following stated.Exemplary substituting group comprises one or more following groups: hydroxyl, acyl group, acyloxy, alkoxyl group, alkene oxygen base, alkynyloxy group, aryloxy, halogen, amide group, amino, cyano group, ketal, acetal, ester and the ether of the alkyl of alkyl, replacement, hydroxyl, protection.
Term " heteroaryl ", as used separately at this or as the part of other group, being illustrated at least one ring and having the aromatic group of at least one heteroatomic optional replacement, and preferably have 5 or 6 atoms at each ring.This heteroaryl preferably has 1 or 2 Sauerstoffatom and/or 1 to 4 nitrogen-atoms in ring, and is connected to the remainder of molecule by carbon.Exemplary heteroaryl comprises furyl, benzofuryl ， oxazolyl ， isoxazolyl ， oxadiazolyl benzoxazolyl, Ben Bing oxadiazolyl, pyrryl, pyrazolyl, imidazolyl, triazolyl, tetrazyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indyl, pseudoindoyl, indolizine base, benzimidazolyl-, indazolyl, benzotriazole base, tetrazolo pyridazinyl, carbazyl, purine radicals, quinolyl, isoquinolyl, imidazopyridyl etc.Exemplary substituting group comprises one or more following groups: alkyl, the alkyl of replacement, hydroxyl, the hydroxyl of protection, acyl group, acyloxy, alkoxyl group, alkene oxygen base, alkynyloxy group, aryloxy, halogen, amide group, amino, cyano group, ketal, acetal, ester and ether.
Term as herein described " hydrocarbon " and " alkyl " have been described the organic compound or the group that are only made up of elemental carbon and hydrogen.These parts comprise alkyl, thiazolinyl, alkynyl and aryl moiety.These parts also comprise the alkyl, thiazolinyl, alkynyl and the aryl moiety that are replaced by other aliphatics or cyclic hydrocarbon group, as alkaryl, and alkene aryl and alkynes aryl.Unless otherwise described, these parts preferably include 1 to 20 carbon atom.
" alkyl of replacement " as herein described part be the hydrocarbyl portion being replaced by least one non-carbon atom, comprises following part, wherein carbochain atom by heteroatoms as nitrogen, oxygen, silicon, phosphorus, boron, sulphur, or halogen atom replacement.These substituting groups comprise halogen, heterocyclic radical, alkoxyl group, alkene oxygen base, aryloxy, hydroxyl, the hydroxyl of protection, acyl group, acyloxy, nitro, amino, amide group, nitro, cyano group, ketal, acetal, ester and ether.
Term used herein " hydroxyl protecting group " represents to protect the group of free hydroxyl group (" protection hydroxyl "), and it in reaction (this reaction is protected) afterwards, can be removed and does not affect the remainder of molecule.
In the time introducing the element of the present invention or its preferred embodiment, article " ", " one ", " being somebody's turn to do " and " described " refers to and has one or more elements.Term " comprises ", and " comprising " and " having " are interpreted as and are included, and refer to other element that can exist outside institute's column element.
Because can carry out various changes and not depart from scope of the present invention above-claimed cpd, product and method, should understand the material comprising in all above-mentioned specification sheetss and following examples should be interpreted as illustrative and be not restriction the meaning.
Embodiment
Following examples are described different aspect of the present invention.
Embodiment 1-prepares Sinomenine derivate
The route of synthesis of preparing Sinomenine derivate is shown in following reaction scheme 2.
Tuduranine can be converted into compound 2-1 by catalytic hydrogenation.That is to say, can be by tuduranine and H 2, Pd/C contacts at high temperature.Compound 2-1 can contact with chloroformic acid vinyl acetate or chloroformic acid 1-chloroethene ester under the existence of aprotic solvent, then at weak acid or weak base, as NaHCO 3dilute solution in be hydrolyzed, to form compound 3-1.Compound 3-1 can use cyclopropyl CH 2x (wherein X is halogen) alkylation or available cyclopropyl CHO carry out reduction amination to form compound 4-1.Compound 4-1 can react to form compound 5-1 with the X of 2 equivalents.Can be by highly basic (, the pKa > 13 having), as NaOH, the reactive mixture before being added into is to form compound 6-1.Compound 6-1 can with alcohol scavenging agent, as POCl 3, and strong acid (the pKa < 0, having) reaction is to form compound 7-1.
Embodiment 2-adds TEA and carries out bromination
Low temperature to bromination reaction be added on low temperature be the alkali of liquid as triethylamine, then aqueous sodium hydroxide solution cancellation, the HBr producing in neutralization reaction.This prevents that this acid from reacting with product, because this reaction soln is warmed to the temperature that it can mix with aqueous sodium hydroxide solution.In an example, TEA can be added into following bromination reaction 3:
Reaction scheme 3
3.0g dihydro tuduranine is dissolved in to 150mL methylene dichloride in 500mL 3-neck flask.Add 0.12mL methylsulfonic acid (meslic acid).Solution is cooled to-30 DEG C.Slowly add 1.02mL Br 2solution in 10mL methylene dichloride.The bromine adding for first half, bromine color disappears fast.Solution is warmed to-20 DEG C and reaction monitor by HPLC.In the time that the peak of list-bromo intermediate declines end, add 3.79mL triethylamine.This solution becomes brilliant violet look.Then solution is warmed to 0 DEG C.Add the 54.3mL 1N NaOH aqueous solution.Reaction mixture is transferred to separatory funnel.Separate two-phase and methylene dichloride extracting twice again for water.Merge organic layer, by dried over mgso, and isolate the yellow solid (3.55g) containing 14 area % compound 2 and 44 area % compounds 3.The structure of compound 2 and compound 3 obtains mass spectroscopy and NMR Data support.
Embodiment 3-adds TEA and adds 2,3-dimethyl-1,3-butadiene and carry out bromination
Add bromine scavenging agent to the reaction described in reaction scheme 3, as 2,3-dimethyl-1,3-butadiene, then excessive bromine is removed in aqueous sodium hydroxide solution cancellation.This prevents the phenates compound that excessive bromine oxidation forms while adding aqueous sodium hydroxide solution, thereby prevents the formation of height foreign pigment.
3.0g dihydro tuduranine is dissolved in to 150mL methylene dichloride in 500mL 3-neck flask.Add 0.12mL methylsulfonic acid.Solution is cooled to-30 DEG C.Slowly add 1.02mL Br 2solution in 10mL methylene dichloride.The bromine adding for first half, bromine color disappears fast.Solution is warmed to-20 DEG C and reaction monitor by HPLC.In the time that the peak of list-bromo intermediate declines end, add 2.78mL triethylamine.This solution becomes brilliant violet look.Then add 0.31mL 2,3-dimethyl-1,3-butadiene.The color of solution is thin out is brownish dark green.Then solution is warmed to 0 DEG C.Add the 54.3mL 1NNaOH aqueous solution.Reaction mixture is transferred to separating funnel.Separate two-phase and methylene dichloride extracting twice again for water.Merge organic layer, by dried over mgso, and be separated into yellow solid (3.39g).
Embodiment 4-is by extract compounds 3 enrichment compounds 2
Compound 2 and compound 3 can, by extracting at organic solvent with alkaline aqueous solution, separate as the solution in the mixture of toluene or toluene and hexane.For example, the product of 1.00g " interpolation TEA and interpolation 2,3-dimethyl-1,3-butadiene carry out bromination " embodiment gained is dissolved in to 150mL toluene.Then the solution extraction with the dense ammonium hydroxide of 50mL and 50mL water by this solution.Then the solution extraction with the dense ammonium hydroxide of 25mL and 75mL water by toluene layer.Then the solution extraction with the dense ammonium hydroxide of 15mL and 85mL water by toluene layer.Merge three layers of aqueous extraction layer.HPLC analyzes and shows that the preferential extraction of compound 3 enters water layer.Again toluene layer is as above carried out to three extractions.HPLC analyzes and shows only there is the compound 3 of negligible quantity in water layer.Under vacuum, separate 20mL toluene from toluene layer.Add 50mL hexane.This organic solution is by extracting above.HPLC analyzes and shows that the preferential extraction of compound 3 enters water layer.Organic layer is by dried over mgso and be separated into the brown oil of 0.35g containing 23 area % compound 2 and 15 area % compounds 3.Merge available from first and the water layer of Tr row extraction.Under vacuum, remove excess of ammonia.Then by aqueous solution dichloromethane extraction three times.Combined dichloromethane layer, by dried over mgso, and is separated into the main gluing solid of 0.23g containing compound 3.
Embodiment 5-prepares the bromo-dihydro tuduranine of 1-
Dihydro tuduranine can become the bromo-dihydro tuduranine of 1-(compound 4) according to the single bromination of reaction scheme 4:
Reaction scheme 4:
3.0g dihydro tuduranine is dissolved in to 150mL methylene dichloride in 500mL 3-neck flask.Add 0.12mL methylsulfonic acid.Solution is cooled to-30 DEG C.Slowly add 0.44mL Br 2solution in 10mL methylene dichloride.Bromine color disappears fast.Solution is warmed to-20 DEG C and will react stir 15 minutes.Then solution is warmed to 0 DEG C.Add the 10.4mL 1N NaOH aqueous solution.Reaction mixture is transferred to separating funnel.Separate two-phase and methylene dichloride extracting twice again for water.Merge organic layer, by dried over mgso, and be separated into the yellow solid (3.29g) containing 90 area % compounds 4.The structure of compound 4 obtains mass spectroscopy and NMR Data support.
Embodiment 6-prepares the bromo-7-methoxyl group of 1-codeinone (methoxylcodone)
This compound can be prepared according to reaction scheme 5:
Reaction scheme 5
Solution by dihydro tuduranine (1.0g, 3.02mmol, 1.0 equivalents) in 30mL acetonitrile is cooled to approximately-20 DEG C, keeps 10 minutes.Add methylsulfonic acid (1.1mL, 17mmol, 5.6 equivalents) to this cooling solution.This reaction mixture becomes settled solution.To react at-20 DEG C and stir after 5 minutes, drip the solution of bromine (0.65mL, 12.7mmol, 4.2 equivalents) in 6mL acetonitrile.This reaction becomes light brown solution.In the time that bath temperature is increased to 0 DEG C gradually, changes this bath into ice bath and will react maintenance in ice bath and stir 1 hour; Then reaction is by adding 1.2g powder KOH cancellation; This reaction is warmed to ambient temperature overnight gradually.Filter reaction mixture, acetonitrile for solid (3 x 20mL) washing; Filtrate and washings are merged and evaporated; Resistates is dissolved in to the mixture of 30mL 1.0N NaOH and 150ml 1: 9DCM/EtOAc, 1.0N NaOH (5 x 40mL) washing for organic phase, then use inclined to one side sodium sulfate (sodiummetasulfate) solution washing once, to use anhydrous magnesium sulfate drying.Remove after volatile matter, it obtains pale solid, 0.55g, purity=84%, productive rate=45%.LC-MS：M+1＝406.10。
Embodiment 7-synthesizes the bromo-7-methoxyl group of 1-codeinone 2
About reaction scheme 5, the solution by dihydro tuduranine (5.0g, 15mmol, 1.0 equivalents) in 150mL acetonitrile is cooled to approximately-20 DEG C, keeps 10 minutes.Add methylsulfonic acid (5.5mL, 84.8mmol, 5.7 equivalents) to this cooling solution.This reaction mixture becomes settled solution.To react at-20 DEG C and stir after 5 minutes, drip the solution of bromine (2.5mL, 48.6mmol, 3.2 equivalents) in 30mL acetonitrile.This reaction becomes light brown solution.Be increased to gradually 0 DEG C when bathing temperature, change this bath into ice bath and will react maintenance in ice bath and stir 1 hour; Then reaction is by adding 6g powder KOH cancellation; This reaction is solidified, and becomes white bulk solid; Add 200mL acetonitrile to this reaction.Filter gained mixture and acetonitrile (3x30mL) washing for solid; Filtrate and washings are merged and flash to oily matter.This oily resistates is dissolved in to 120mL ethyl acetate; Gained solution washs and uses anhydrous magnesium sulfate drying with 1N NaOH solution (5x80mL).Remove after volatile matter, it obtains 2.3g white solid, productive rate=38% and purity=85%.
Embodiment 8-synthesizes the bromo-7-methoxyl group of 1-hydrocodone 3
About reaction scheme 5, bromo-200mg 1-7-methoxyl group codeinone is dissolved in to the 10mL KH of pH=7 2pO 4/ K 2hPO 4in damping fluid.Gained solution spends the night in 35 DEG C of hydrogenations under 60psi hydrogen under the existence of Wilkinson catalyzer.Be cooled to after room temperature, remove volatile matter.It obtains the brown mixture containing required product.LC-MS：M+1＝408.14。

Claims (9)

1. the compound of formula (I):
Wherein:
R 1for alkyl;
R 2and R 3independently selected from hydrogen, halogen, OH, NH 2and CN;
R 4be selected from halogen, NH 2, CN and OR 4a;
R 4afor forming the key containing ether ring part;
R 5and R 6independently selected from hydrogen, OH, NH 2and SH, wherein R 5and R 6can form together and be selected from following group :=NOH ,=S ,=CHR 5awith-O (CH 2) 2o-;
R 5abe selected from hydrogen and halogen;
R 7be selected from hydrogen and OR 7a;
R 7afor alkyl;
R 8for hydrogen;
R 9and R 10for hydrogen;
R 11and R 12in the time existing independently selected from hydrogen, OH and halogen;
Y is selected from alkyl and alkyl-carbonyl;
M is 0 to 8 integer;
And the optical activity of wherein said compound is (+),
Wherein
Term " alkyl " refers to following group, and it is low alkyl group of comprising 1 to 8 carbon atom at main chain, and is up to 20 carbon atoms, and its can be straight or branched or ring-type.
2. compound claimed in claim 1, wherein:
R 1be selected from alkyl, cyclopropyl and the cyclobutyl with 1 to 8 carbon atom;
R 2be selected from hydrogen and halogen;
R 4for OR 4a;
R 5and R 6independently selected from hydrogen, OH and NH 2;
R 3, R 11and R 12the hydrogen of respectively doing for oneself;
Y is {-} CH 2{-}; With
M is 0.
3. the compound of formula (Ia):
Wherein:
R 2be selected from hydrogen and halogen;
R 5and R 6independently selected from hydrogen, OH and NH 2, wherein R 5and R 6can form together=O;
R 7be selected from hydrogen and OR 7a; With
R 7afor alkyl, wherein term " alkyl " refers to following group, and it is low alkyl group of comprising 1 to 8 carbon atom at main chain, and is up to 20 carbon atoms, and its can be straight or branched or ring-type.
4. the compound of formula (Ib):
Wherein:
R 2be selected from hydrogen and halogen;
R 4for OR 4a;
R 4afor hydrogen;
R 5and R 6independently selected from hydrogen, OH and NH 2;
R 7be selected from hydrogen and OR 7a; With
R 7afor alkyl, wherein term " alkyl " refers to following group, and it is low alkyl group of comprising 1 to 8 carbon atom at main chain, and is up to 20 carbon atoms, and its can be straight or branched or ring-type.
5. the compound of formula (Ic):
Wherein:
R 2be selected from hydrogen and halogen;
R 4for OR 4a;
R 4afor hydrogen; With
R 5and R 6independently selected from hydrogen and NH 2, or R wherein 5and R 6can form together=O,
The optical activity of wherein said compound is (+).
6. compound, it is selected from compound number 8-1,9-1,10-1,11-1,12-1 and 13-1, and wherein X is halogen, and the optical activity of wherein said compound is (+):
7. prepare the method for compound 7 according to following reaction scheme:
Wherein:
R 1for alkyl or vinyl;
R 2and R 3independently selected from hydrogen, halogen, OH, NH 2, CN and alkyl;
R 4and R 5independently selected from hydrogen, OH, NH 2and SH, or R wherein 4and R 5can form together and be selected from following group :=O ,=NOH ,=S ,=CHR 5awith-O (CH 2) 2o-;
R 5abe selected from hydrogen and halogen;
R 6for hydrogen and alkyl;
R 7and R 8independently selected from hydrogen, OH, NH 2and SH, or R wherein 7and R 8can form be together selected from=O and=group of S;
X is halogen;
Y is selected from alkyl, carbonyl and alkyl-carbonyl; With
Z is selected from {-} O{-} and {-} NH{-};
Wherein
Term " alkyl " refers to following group, and it is low alkyl group of comprising 1 to 8 carbon atom at main chain, and is up to 20 carbon atoms, and its can be straight or branched or ring-type;
And the optical activity of wherein said compound 7 is (+).
8. method claimed in claim 7, wherein:
R 1be selected from alkyl, vinyl, cyclopropyl and the cyclobutyl with 1 to 8 carbon atom;
R 4and R 5independently selected from hydrogen and OH, or R wherein 4and R 5can form be together selected from following group :=O ,=NOH and-O (CH 2) 2o-;
R 7and R 8independently selected from hydrogen, OH and NH 2, or R wherein 7and R 8can form together=O;
X is selected from bromine and chlorine;
Y is selected from {-} CH 2{-} and {-} CO{-}; With
Z is {-} O{-}.
9. the method described in any one in claim 7 to 8, wherein compound 2 is 1: 2: 1 to 1: 20: 20 with the weight ratio of chloroformic acid vinyl acetate or chloroformic acid 1-chloroethene ester and proton acceptor or protophobe, the reaction of steps A is carried out under the existence of aprotic solvent, and temperature range is 50 DEG C to 120 DEG C; Compound 3 and R 1yX or R 1the weight ratio of Y is 1: 1 to 1: 3, and the reaction of step B is carried out under the existence of aprotic solvent, and temperature range is 20 DEG C to 100 DEG C; Compound 4 and X 2weight ratio be 1: 2 to 1: 2.5, the reaction of step C is carried out under the existence of organic solvent, and temperature range is-30 DEG C to 0 DEG C; Compound 5 is 1: 1.5 to 1: 20 with the weight ratio of proton acceptor, and the reaction of step D is carried out under the existence of aprotic solvent and/or protonic solvent, and temperature range is-30 DEG C to 0 DEG C; And compound 6 is 1: 0.5: 2 to 1: 2: 20 with the weight ratio of scavenging agent and protophobe, and the reaction of step e is carried out under the existence of aprotic solvent, and temperature range is 0 DEG C to 100 DEG C; The optical activity of compound 2,3 and 4 is (+), and the configuration of C13, C14 and C9 is selected from respectively RRS, RSS, SRR and SSR; And the optical activity of compound 5,6 and 7 is (+), and the configuration of C5, C13, C14 and C9 is selected from respectively RRRS, RRSS, SRRS, SRSS, RSRR, RSSR, SSRR and SSSR.
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